Leflunomide

All congenital malformations (majors, minors, majors and minors, or unspecified)

id	Study   Auto Bérard, 2018Karadag, 2013Viktil (Controls exposed to other treatments), 2012Viktil (Controls unexposed, NOS), 2012Chambers (Unexposed control, disease free), 2010Chambers (Unexposed control, sick), 2010	Lib. in paper	Exposition period  Auto during pregnancy (anytime or not specified)1st trimester2nd trimester3rd trimester2nd and/or 3rd trimesterthroughout pregnancyearly pregnancydays before deliverylate pregnancypreconception-onlypericonceptionalpreconceptional for kinetic reasonat least 1st trimester3 months (or more) before pregnancy or during pregnancy1st and 2nd trimester3 months or more before pregnancy or1st trimester	Study type  All studies Case control excluded Only case control	Control type    Auto unexposed (general population or NOS)unexposed, sickunexposed, disease freeexposed to other treatment, sicknot specifiedsiblingwhatever (meta-analysis)	Tags	OR 95%CI	x1/n1 x0/n0	no cases	no exposed	ROB	Ref.
S2900 R11320	Bérard, 2018	Major congenital malformations	1st trimester	nested case control	unexposed (general population or NOS)	Adjustment: Yes	0.97 [0.81;1.16]	5/51   14,363/144,265	14,368	51		ref
S4080 R11323	Karadag, 2013	Major malformations	early pregnancy	retrospective cohort	unexposed, sick	Adjustment: No	5.00 [0.07;366.35] C	0/2   0/8	0	2		ref
S13720 R53450	Viktil (Controls exposed to other treatments), 2012	Major malformations	3 months or more before pregnancy or1st trimester	population based cohort propective	exposed to other treatment, sick excluded	Adjustment: No	9.30 [0.37;231.05] C excluded (control group)	0/2   50/1,459	50	2		ref
S13721 R53452	Viktil (Controls unexposed, NOS), 2012	Major malformations	3 months or more before pregnancy or1st trimester excluded	population based cohort propective	unexposed (general population or NOS)	Adjustment: No	10.00 [0.41;245.45] C excluded (exposition period)	0/2   5,000/154,976	5,000	2		ref
S2970 R11321	Chambers (Unexposed control, disease free), 2010	Major structural defects (live births and pregnancy losses)	1st trimester	prospective cohort	unexposed, disease free excluded	Adjustment: No	1.20 [0.23;6.17] C excluded (control group)	3/63   3/75	6	63		ref
S2969 R11322	Chambers (Unexposed control, sick), 2010	Major structural defects (live births and pregnancy losses)	1st trimester	prospective cohort	unexposed, sick	Adjustment: No	0.71 [0.18;2.84] C	3/63   7/106	10	63		ref
					Total	3 studies	0.97 [0.81;1.16]		14,378	116
x1: number of endpoints among exposed, n1: number of exposed; x0: number of endpoints among non exposed, n0: number of non exposed; C: calculated odds ratio from numbers of events and effectives

Forest plot

Sensitivity analysis

Publication bias and p-hacking diagnosis

Sub-groups analysis using all included studies

excluded 2970, 13720